The training plan outlined in this proposal focuses on elucidating the molecular mechanisms underlying modulation of islet hormone secretion by the two-pore domain K+ channel TALK-1, and defining how these processes contribute to maintenance of glucose homeostasis. Our preliminary findings indicate that TALK-1 channels participate in the pathogenesis of hyperglycemia and obesity; however, the underlying mechanisms contributing to this effect are unknown. Importantly, a non-synonymous polymorphism in TALK-1 is linked to increased type-2 diabetes mellitus (T2DM) susceptibility. We have recently shown that ?-cell TALK-1 channels limit basal and 2nd-phase insulin secretion, and contribute to the development of fasting hyperglycemia in response to the chronic metabolic stress of a high-fat diet (HFD). While these observations indicate that TALK- 1 channels serve a critical role in the maintenance of glucose homeostasis, little else is known about the regulation or physiological roles of TALK-1 channels. This presents a major obstacle to determining how TALK- 1 channels impact the pathogenesis of T2DM. Our strong preliminary findings indicate that TALK-1 channel modulation of basal insulin secretion impacts hepatic insulin sensitivity in the context of chronic metabolic stress. Moreover, we find that mice lacking TALK-1 channels are protected from HFD-induced obesity, with reduced body weight and adiposity relative to control mice evident shortly after being placed on a HFD. Our preliminary data show that this is likely caused by the reduced food intake of TALK-1 KO mice fed a HFD. The goal here is to define how TALK-1 channel modulation of islet hormone secretion impacts metabolic homeostasis. We hypothesize that TALK-1 channel-dependent modulation of islet hormone secretion controls hepatic glucose production and food intake. I will test the central hypothesis by determining the mechanisms by which TALK-1 channels modulate islet hormone secretion through in vitro studies of transgenic mouse and human islet cell function in response to secretagogues (Aim 1). These findings will be extended to detailed studies of how TALK-1 channels contribute to the development of hyperglycemia and obesity in vivo (Aim 2). Successful completion of the proposed research will advance our understanding of the fundamental mechanisms regulating islet cell function. Moreover, elucidating the influence of TALK-1 channels on diet- induced obesity and hyperglycemia will greatly expand comprehension of the mechanisms underlying TALK- 1's contributions to the pathogenesis of T2DM. Through this fellowship application, I will develop 1) a novel understanding of the regulation and physiological functions of islet TALK-1 channels, and 2) my potential as an independent investigator focused on enteroendocrine cell function. These training goals will be facilitated by the detailed research plan, the exceptionally qualified mentors with expertise in th proposed study design, and the outstanding facilities and training resources available through Vanderbilt University.